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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Benzimidazolone Activators of Chloride Secretion: Potential Therapeutics for Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Sangeeta Singh, Colin A. Syme, Ashvani K. Singh, Daniel C. Devor and Robert J. Bridges
Journal of Pharmacology and Experimental Therapeutics February 2001, 296 (2) 600-611;
Sangeeta Singh
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Colin A. Syme
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Ashvani K. Singh
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Daniel C. Devor
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Robert J. Bridges
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Abstract

The diseases of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are characterized by mucus-congested airways. Agents that stimulate the secretion of Cl− are anticipated to facilitate mucociliary clearance and thus be of benefit in the treatment of CF and COPD. Recently 1-EBIO (1-ethyl-2-benzimidazolinone or 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) was shown to stimulate chloride secretion albeit at relatively high concentrations (0.6–1 mM). The studies reported here were undertaken to develop a more potent benzimidazolone. Structure activity studies with 30 benzimidazolone derivatives revealed that ethyl and hydrogen groups at the 1 and 3 nitrogen positions, respectively, were critical for the activation of hIK1 K+ channels and that other alkyl groups were not tolerated at these positions without some loss in potency. Substitutions at the 5 and 6 positions improved the potency of 1-EBIO. Compared with 1-EBIO, the most potent of these derivatives, DCEBIO (5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) was severalfold better in a 86Rb+ uptake assay, 20-fold better in short circuit current measurements on T84 monolayers, and 100-fold better in patch-clamp assays of hIK1 activity. Short circuit current studies revealed DCEBIO stimulates Cl−secretion via the activation of hIK1 K+ channels and the activation of an apical membrane Cl− conductance. The improved potency of DCEBIO strengthens the possibility that compounds in this class may be of therapeutic benefit in the treatment of CF and COPD.

Footnotes

    • Received July 24, 2000.
    • Accepted October 19, 2000.
  • Send reprint requests to: Robert J. Bridges, Ph.D., S310 BST, 3500 Terrace St., Cell Biology & Physiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261. E-mail:bbridges+{at}pitt.edu

  • This work was supported by Cystic Fibrosis Foundation Grants FRIZZE97RO and BRIDGE00G0 and by National Institutes of Health Grant 1RO1DK54941.

  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 2
1 Feb 2001
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Benzimidazolone Activators of Chloride Secretion: Potential Therapeutics for Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Sangeeta Singh, Colin A. Syme, Ashvani K. Singh, Daniel C. Devor and Robert J. Bridges
Journal of Pharmacology and Experimental Therapeutics February 1, 2001, 296 (2) 600-611;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Benzimidazolone Activators of Chloride Secretion: Potential Therapeutics for Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Sangeeta Singh, Colin A. Syme, Ashvani K. Singh, Daniel C. Devor and Robert J. Bridges
Journal of Pharmacology and Experimental Therapeutics February 1, 2001, 296 (2) 600-611;
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